This project will measure the integrity of muscarinic signal transduction and indices of molecular plasticity within the septal- hippocampal cholinergic system in age- and lesion-induced states of the rat brain. Lesions will model neurodegeneration within the excitatory entorhinal input or the cholinergic septal input to the hippocampus of both normal (young) adults and aged adults. The primary assays of muscarinic receptor function in the aged or lesioned hippocampus will be phosphoinositide (PI) metabolism for postsynaptic receptors and modulation of acetylcholine release for presynaptic receptors. The coupling of muscarinic receptors to cyclic AMP inhibition will also be studied. The responses of each of these systems to full and partial agonists will be quantitated in groups of animals behaviorally evaluated for aging- or lesion-induced memory dysfunction. A special pharmacological focus will be the measurement of coupling efficiencies and relative contribution to the m1 and m3 systems to hippocampal PI metabolism in aging- and lesion-induced states of the brain. Plasticity in the signal transduction systems will also be assessed at the molecular level by quantitating the levels of MRNA molecules for each of the five muscarinic receptor subtypes in the hippocampus and medial septal area with a method of quantitative polymerase chain reaction (PCR). Alterations in muscarinic signal transduction will be correlated with other molecular indices of plasticity in the hippocampus and medial septal area. In the hippocampus the additional plasticity indices include MRNA for the growth-associated protein GAP-43, nerve growth factor (NGF), interleukin-1 beta and interleukin-3. In the basal forebrain the auxiliary plasticity indices include the MRNA molecules for the phenotypic enzyme choline acetyltransferase (CAT), the NGF receptor, GAP-43, and forms of the beta-amyloid precursor protein. Gap- 43 may be induced in either brain region in relationship to alterations in cholinergic or glutamatergic neurotransmission in aging or hippocampal deafferentation. Hippocampal NGF may be involved in the induction of MRNA molecules within the septal cholinergic systems, including GAP-43, beta-amyloid protein, CAT, and NGF receptor. Thus, the study of these molecular and pharmacological markers will allow assessment of the involvement the NGF and interleukin systems with the survival, functional plasticity, and molecular plasticity of the septal- hippocampal cholinergic system.